ClinVar Miner

Submissions for variant NM_000051.4(ATM):c.2927T>C (p.Val976Ala) (rs146145357)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166813 SCV000217627 likely benign Hereditary cancer-predisposing syndrome 2018-04-18 criteria provided, single submitter clinical testing In silico models in agreement (benign);Subpopulation frequency in support of benign classification
Invitae RCV000230218 SCV000282916 uncertain significance Ataxia-telangiectasia syndrome 2019-12-31 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 976 of the ATM protein (p.Val976Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs146145357, ExAC 0.08%). This variant has been reported in an individual affected with breast cancer (PMID: 28503720) and an individual affected with acute myeloid leukemia (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 187123). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000588819 SCV000293347 uncertain significance not provided 2021-04-12 criteria provided, single submitter clinical testing In silico analysis supports that this missense variant does not alter protein structure/function; Identified in individuals with acute myelogenous leukemia, breast, and renal cancer (Lu 2015, Rummel 2017, Yehia 2018); This variant is associated with the following publications: (PMID: 23555315, 28503720, 26689913, 29684080)
Color Health, Inc RCV000166813 SCV000682090 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-07 criteria provided, single submitter clinical testing This missense variant replaces valine with alanine at codon 976 of the ATM protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual affected with breast cancer (PMID: 28503720) and in an individual affected with acute myeloid leukemia (PMID: 26689913). This variant has also been identified in 9/246048 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000588819 SCV000694239 uncertain significance not provided 2017-04-13 criteria provided, single submitter clinical testing Variant summary: The ATM c.2927T>C (p.Val976Ala) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 8/120998 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.00078 (8/10256). This frequency is close to the estimated maximal expected allele frequency of a pathogenic ATM variant (0.0010005), suggesting this variant may be a benign polymorphism found primarily in the populations of African origin. The variant has been reported in the literature, without strong evidence for causality. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Counsyl RCV000230218 SCV000799924 uncertain significance Ataxia-telangiectasia syndrome 2018-05-14 criteria provided, single submitter clinical testing
Mendelics RCV000230218 SCV000838513 uncertain significance Ataxia-telangiectasia syndrome 2018-07-02 criteria provided, single submitter clinical testing
Athena Diagnostics Inc RCV000588819 SCV001879413 uncertain significance not provided 2021-06-02 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.